Process and intermediates to prepare17beta-hydroxy-7alpha-methyl-19-nor-17alpha-pregn -5(10)-en-20-yn-3-one

ABSTRACT

The present invention is a process for the preparation of 17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one (17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one, tibolone) of formula 1, which comprises hydrolysis of 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene  3,3 -cyclic ketals of formula 2, where groups R 1 , R 2 , R 3  and R 4  are hydrogen atoms or alkyl groups, or R 1  and R 3 , taken together with the carbon atoms within the dioxolane ring to which they are attached, form an alicyclic ring fused to the dioxolane ring, with R 2  and R 4  being hydrogen atoms, or R 1  and R 3  together with the carbon atoms to which they are attached form an aromatic ring fused to the dioxolane ring, where R 2  and R 4 , taken together, form a chemical bond within said aromatic ring. In addition, the present invention includes an intermediate, compound of formula 2 and two processes to prepare 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene  3,3 -cyclic ketals of formula 2: (a) by contacting 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one with vicinal diols in the presence of a protic acid, and (b) by contacting 7α-methyl-5(10)-estrene-17-one 3,3-cyclic ketals of formula 4, where R 1 -R 4  are defined as above, with metal acetylides, in inert solvents.

CROSS REFERENCES TO RELATED APPLICATION

This application is a national phase application based upon priorityInternational PCT Patent Application No. PCT/PL2003/000099 filed Oct. 1,2003, International Publication No. WO 2004/031204 A2 published Apr. 15,2004, which is based upon priority Polish Application P35465 filed Oct.4, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is a process, including intermediates, to producetibolone (17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one;17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one), a pharmaceuticalagent useful in treating postmenopausal conditions and for theprevention of osteoporosis.

2. Description of the Related Art

Dutch patent NL 6,406,797 discloses tibolone and a process for itspreparation which comprises hydrolysis of the enol ether groupingpresent in17α-ethynyl-17β-hydroxy-3-methoxy-7α-methyl-2,5(10)-estradiene.17α-Ethynyl-17β-hydroxy-3-methoxy-7α-methyl-2,5(10)-estradiene wasprepared in three synthetic steps from17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene on the way of aBirch reduction to the 2,5(10)-diene, followed by an Oppenauer oxidationat C(17) and an acetylide addition to the C(17)-carbonyl.

Helvetica Chim. Acta 50, 1453 (1967) describes a reaction sequenceleading from 17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene to17α-ethynyl-17β-hydroxy-3-methoxy-7α-methyl-2,5(10)-estradiene which wasthen hydrolyzed to tibolone.

J. Am. Chem. Soc. 86, 742 (1964) and Helvetica Chim. Acta 50, 289 (1967)disclose the preparation of17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene from readilyavailable testosterone 17-esters in ca. eight synthetic steps.

Tetrahedron Lett. 38, 7997 (1997) and Italian patent application IT2000MI0918 A1 both describe the preparation of17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene in two steps from17β-tetrahydropyranyloxy-3-methoxy-1,3,5(10)-estratrien-6-one, which isreadily derived from β-estradiol in four synthetic steps.

Italian patent application IT 99MI2128 A1 describes the route totibolone via the 3,3-dimethoxy derivative,3,3-dimethoxy-17αethynyl-17β-hydroxy-7α-methyl-5(10)-estrene, which isobtained in 6 steps from17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene.

International Patent Application PCT/EP/99/07768 discloses a process forhigh purity, highly stable tibolone preparation which compriseshydrolysis of the 3,3-dimethylketal grouping present in3,3-dimethoxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene.3,3-Dimethoxy-17α-ethynyl-17α-hydroxy-7α-methyl-5(10)-estrene was theonly 3,3-ketal used and claimed as a substrate for the hydrolysisreaction by which tibolone was prepared.

Recl. Trav. Chim. Pays-Bas 105, 111 (1986) discloses a process fortibolone preparation which comprises hydrolysis of the 3,3-dimethylketalgrouping present in3,3-dimethoxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene.3,3-Dimethoxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene was theonly 3,3-ketal used as a substrate for the hydrolysis reaction by whichtibolone was prepared.3,3-Dimethoxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene wasprepared in eight synthetic steps from17β,19-diacetoxy-4,6-androstadien-3-one. A four-step preparation of17β,19-diacetoxy-4,6-androstadien-3-one from readily available3β,17β-diacetoxy-5-androstene is disclosed in Experientia 18, 464 (1962)and in Belgian patent BE 620,225.

A process to prepare 7α-methyl-19-oxo-4-androst-3,17-dione in 4 stepsfrom 17β,19-diacetoxy-4,6-androstadien-3-one (or in eight steps from thereadily available 3β,17β-diacetoxy-5-androstene) is also disclosed inRecl. Trav. Chim. Pays-Bas 105, 111 (1986).

U.S. Pat. No. 3,475,465 discloses a one step preparation of tibolonefrom 7-methyl-19-oxo-4-androst-3,17-dione in the presence of potassiummetal and acetylene in liquid ammonia, albeit the yield was notspecified and for a closely related compound the yield was below 50%.

U.S. Pat. No. 3,928,398 discloses a process to prepare17β-hydroxy-7α-methyl-4-estren-3-one from 19-nortestosterone in foursteps.

J. Med. Chem. 35, 2113 (1992) describes the preparation of3,3-ethylenedioxy-7α-methyl-5(10)-estren-17-one in two synthetic stepsfrom 17β-hydroxy-7α-methyl-4-estren-3-one. The conditions to obtain3,3-ethylenedioxy-17β-hydroxy-7α-methyl-5(10)-estrene in one step from17β-hydroxy-7α-methyl-4-estren-3-one and ethylene glycol are alsodescribed. This publication also discloses a highly efficient hydrolysisreaction of 3,3-ethylenedioxy-15α-hydroxy-7α-methyl-5(10)-estren-17-oneto 15α-hydroxy-7α-methyl-4-estren-3,17-dione, under the conditions ofHCl in MeOH.

Synthesis 501 (1981) reviews examples of acid catalyzed ketal (acetal)preparation from carbonyl compounds and alcohols, including 1,2-diols.

J. Org. Chem. 54, 5180 (1989) describes a preparation of3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-5-androstene from17α-ethynyl-17β-hydroxy-4-androsten-3-one (ethisterone) and ethyleneglycol, in the presence of p-toluenesulfonic acid and trimethylorthoformate.

German Patent DE 3,337,179 describes the preparation of a mixture of3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-5-estrene and3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-5(10)-estrene by contacting17α-ethynyl-17β-hydroxy-4-estren-3-one with ethylene glycol, in thepresence of trimethyl orthoformate and p-toluenesulfonic acid, in adichloromethane solution.

U.S. Pat. No. 3,904,611 discloses the preparation of17β-acetoxy-3,3-ethylenedioxy-5(10)-estrene by reaction of17β-acetoxy-4-estren-3-one with ethylene glycol, in the presence ofp-toluenesulfonic acid, under reflux for 16 hours.17β-Acetoxy-3,3-ethylenedioxy-5(10)-estrene was then hydrolyzed in thepresence of malonic acid, in an acetone-water mixture.

Synthetic Commun. 27, 2197 (1997) addresses the issue of the selectivityobserved in the reaction of 19-norsteroidal 4-en-3-ones with ethyleneglycol, in the presence of various catalysts. The ratio of3,3-ethylenedioxy-5,6-elkenes to 3,3-ethylenedioxy-5(10)-elkenes variedfrom 50:50 to 0:100, depending on the catalyst.

Recl. Trav. Chim. Pays-Bas 92, 1047 (1973) addresses the issue of theselectivity observed in the reaction of steroidal 4-en-3-ones withethylene glycol, catalyzed by various acids. Importantly, the formationof steroidal 4,5-unsaturated 3,3-ethylenedioxy ketals versus5,6-unsaturated 3,3-ethylenedioxy ketals was correlated with pKa valuesof the acids. 4,5-Unsaturated 3,3-ethylenedioxy products were obtainedexclusively in cases when protic acids with pKa value above 3 were used.5,6-Unsaturated 3,3-ethylenedioxy products were obtained exclusively incases when a protic acid with pKa value less than ca. 1 was used.

Steroids 60, 414 (1995) reports on the selectivity observed in thereaction of 19-norsteroidal 4-en-3-ones with ethylene glycol, catalyzedby an acid. Accordingly, the ratio of the 5,6-unsaturated3,3-ethylenedioxy product versus the 5(10)-unsaturated 3,3-ethylenedioxyproduct is dependent on reaction time, temperature and acidconcentration, such that less vigorous conditions favor the formation ofthe 5,6-alkene.

U.S. Pat. No. 4,308,265 discloses a process to prepare17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one(7α-methylnorethindrone) and its esters. Thus,17α-ethynyl-17β-hydroxy-3-methoxy-7α-methyl-2,5(10)-estradiene wasprepared from 3-methoxy-7α-methyl-1,3,5(10)-estratrien-17-one. U.S. Pat.No. 4,308,265 discloses also that3,3-ethylenedioxy-7α-methyl-5(10)-estren-17-one was ethynylated at C(17)and a 17-ethynyl-17-hydroxy compound thus obtained was then hydrolyzedwith dilute hydrochloric acid to a crystalline enone, which wasesterified by heptanoic anhydride to yield 7α-methylnorethindroneenanthate, which is a steroidal 4-en-3-one, and not a 5(10)-en-3-one.The structures of the intermediates in this route to7α-methylnorethindrone enanthate were not supported by anyphysicochemical or other data. Also, no experimental details were givenfor the ketalization step. In light of the prior art cited aboveregarding the various positional isomers of alkenes which may form uponketalization of 4-en-3-ones, when the conditions are not carefullycontrolled, the alternative structures of3,3-ethylenedioxy-7α-methyl-5-estren-17-one or3,3-ethylenedioxy-7α-methyl-4-estren-17-one are very likely as theintermediates on the way to 7α-methylnorethindrone esters as describedin U.S. Pat. No. 4,308,265, especially that a purification of the ketalspecies is not described. Also, patent application U.S. Pat. No.4,308,265 does not give any indication that the hydrolysis of3,3-ethylenedioxy-17α-ethynyl-17-hydroxy-7α-methyl-5(10)-estrene in thepresence of an acid may lead to 3-keto-5(10-estrene derivatives.

East Germany Patent DD 143,781 describes efficient oxidation of17β-hydroxy-3,3-dimethoxy steroids to 3,3-dimethoxy-17-ketosteroidsunder the conditions of pyridinium chlorochromate and sodium acetate indichloromethane.

European Patent Application EP 0 700 926 A1 discloses a process for thepreparation of gestodene. Disclosed is an Oppenauer oxidation of amixture of 3,3-ethylenedioxy-17β-hydroxy-18-methyl-5-estrene and3,3-ethylenedioxy-17β-hydroxy-18-methyl-5(10)-estrene to a mixture of3,3-ethylenedioxy-18-methyl-5-estren-17-one and3,3-ethylenedioxy-18-methyl-5-estren-17-one. In the final step ofgestodene synthesis, a mixture of a 3,3-ethylenedioxy-5-ene and a3,3-ethylenedioxy-5(10)-ene is hydrolyzed in the presence of acid,affording exclusively gestodene, which is a 19-norsteroidal 4-en-3-one.

U.S. Pat. Nos. 3,318,928 and 4,874,754 both give examples of thereaction of steroidal 17-ketones with metal acetylides, leading to17α-ethynyl-17-hydroxy derivatives.

U.S. Pat. No. 2,806,030 discloses a process for the preparation of17α-ethynyl-19-nortestosterone. Thus,3,3-ethylenedioxy-5(10)-estren-17-one in the presence of potassiumalkoxide and acetylene afforded3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-5(10)-estrene.3,3-Ethylenedioxy-17α-ethynyl-17β-hydroxy-5(10)-estrene was hydrolyzedin acidic medium to 17α-ethynyl-19-nortestosterone, which is a19-norsteroidal 4-en-3-one.

UK Patent Application GB 2,185,257 A describes a mild hydrolysis of17β-acetoxy-3,3-ethylenedioxy-6β-methyl-5(10)-estrene, which in thepresence of acetic acid, water and diethyl ether afforded17β-acetoxy-3,3-methyl-5(10)-estren-3-one.

J. Org. Chem. 43, 1821 (1978) disclosed a general procedure for thehydrolysis of β,γ-unsaturated ketals, under the conditions of 80%aqueous acetic acid.

Synthetic Commun. 25, 395 (1995) describes a method for the cleavage ofketals (acetals) using CuSO₄ adsorbed on silica gel. Two examples ofsteroidal 3,3-ethylenedioxy-5-enes are given. Each of these ketals, whentreated with CuSO₄ adsorbed on silica gel in a chloroform solution,afforded respective steroidal 4-en-3-one as the only products. Noβ,γ-unsaturated ketones formed from the 3,3-ethylenedioxy-5-enes.

BRIEF SUMMARY OF INVENTION

Disclosed is a process for the preparation of17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one of formula1, which comprises:

-   (I) hydrolysis of 17α-ethynyl-17β-hydroxy-7-methyl-5(10)-estrene    3,3-cyclic ketals of formula 2, where:    -   (1) each of R₁, R₂, R₃ and R₄ is a hydrogen atom or a C₁₋₄alkyl        group, or    -   (2) R₁ and R₃ are taken together to form an alicyclic ring        together with the carbon atoms in the dioxolane ring to which        the groups are attached and R₂, R₄ are hydrogen atoms, or    -   (3) R₁ and R₃ are taken together to form an aromatic ring        together with the carbon atoms in the dioxolane ring to which        they are attached, and R₂, R₄ are taken together to form a        chemical bond participating in the aromatic electron system of        the aromatic ring formed by R₁ and R₃, in the presence of salts        of transition metals, salts of lithium or salts of magnesium,        and    -   (b) separating        17β-hydroxy-7β-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one        obtained in step (a) from        17β-hydroxy-7α-methyl-19-nor-17α-pregn-4-en-20-yn-3-one        by-product of formula 3; and    -   (c) converting        17β-hydroxy-7α-methyl-19-nor-17α-pregn-4-en-20-yn-3-one obtained        as a by-product in step (b) to the ketal of formula 2, wherein        R₁-R₄ are defined as above, which is then hydrolyzed to        17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one in        step (a).

A more detailed description of the invention is provided in thefollowing description and appended claims taken in conjunction with theaccompanying drawing.

BRIEF DESCRIPTION OF THE DRAWING

The drawing is a chart of a process for tibolone synthesis by hydrolysisof 3,3-ketals of formula 2 and illustrating chemical formulas 1, 2, 3and 4.

DETAILED DESCRIPTION OF THE INVENTION

The following is a detailed description and explanation of the preferredembodiments and best modes for embodying the invention along with someexamples thereof.

In a majority of the processes for tibolone synthesis disclosed to date,17-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene is the keyintermediate. The process presented in Dutch Patent NL 6406797 requiresthat 17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene be reducedunder the Birch reduction conditions, then the 17β-hydroxy group isoxidized under the Oppenauer oxidation conditions, followed by anacetylide addition to the 17-ketone, which results in17α-ethynyl-17β-hydroxy-3-methoxy-7α-methyl-2,5(10)-estradiene. Thiscompound is subsequently hydrolyzed under mild acidic conditions,leading to tibolone. In alternative, though related processes (e.g. vanVliet at al. Recl. Trav. Chim. Pays-Bas 105, 111 (1986); patentapplication IT 99MI2128 A1) the 3-keto group is initially protected inthe form of a 3,3-dimethylacetal, then the acetylide addition at C(17)is carried out and, finally, the thus obtained3,3-dimethoxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene ishydrolyzed to tibolone. The deprotection of the unstable dimethylacetal,under very weakly acidic conditions, resulted exclusively or almostexclusively in 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one,while the application of stronger acids led to the 4-ene isomer,17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one. The latter compound,which is a conjugated ketone, often is a ubiquitous impurity oftibolone.

All the disclosed processes for tibolone synthesis which make use of17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene require that thearomatic ring A in this compound be reduced under the Birch conditions(March, J. Advanced Organic Chemistry. Reactions, Mechanisms andStructure. 4^(th) Ed.; John Wiley and Sons; New York, N.Y., 1992; p.781). This reduction method, however, poses technical difficulties andenvironmental hazards due to the need for a large excess of liquidammonia, and due to the use of pyrophoric metals, such as sodium orlithium. Similarly, the synthesis of the key intermediate,17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene, is often veryproblematic because the required starting materials are expensive and/orare not easily accessible. Also, the known conditions necessary for thesynthesis of 17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene areoften troublesome, such as the low temperature LIDAKOR reaction or astep involving large amounts of boron-derived side-products (Tedesco, R.Et al. Tetrahedron Lett. 38, 7997 (1997); patent application IT2000MI0918 A1).

These difficulties are, in part, avoided in the processes for tibolonesynthesis in which 6-dehydro-19-hydroxytestosterone derivatives are usedas the substrate, instead of17β-hydroxy-3-methoxy-7αmethyl-1,3,5(10)-estratriene (van Vliet et al.Recl. Trav. Chim. Pays-Bas 105, 111 (1986); U.S. Pat. No. 3,475,465).However, according to prior art such 19-oxygenated compounds are noteasily accessible, either.

All of the known processes for tibolone synthesis require during thelast step of the synthesis that a hydrolysis of a 3-alkoxy-2,5(10)-dieneor a 3,3-dimethoxy acetal group be carried out, and, importantly, other3,3-ketals (acetals) have not been disclosed to date as substrates fortibolone.

Thus, the number of existing methods suitable for a short, large scalesynthesis of tibolone from commercially available steroids is verylimited. The shortest routes disclosed to date are: (a) the route viathe 3-methoxy-2-ene derivative which is obtained from17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene, which is derivedfrom β-estradiol [NL 6,406,797 and Tetrahedron Lett. 38, 7997 (1997); aten step route] or is derived from testosterone [J. Am. Chem. Soc. 86,742 (1964) and Helvetica Chim. Acta 50, 289 (1967); ca. thirteen steproute], (b) the route to tibolone via the 3,3-dimethoxy derivative,which is obtained in 6 steps from17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene (Italian patentapplication IT 99MI2128 A1), and (c) the route in nine steps from3β,17β-diacetoxy-5-androstene via 7α-methyl-19-oxo-4-androst-3,17-dione[U.S. Pat. No. 3,475,465; Recl. Trav. Chim. Pays-Bas 105, 111 (1986);Experientia 18, 464 (1962)].

These processes are troublesome due to: (a) the need to carry out thetechnologically difficult Birch reduction of17β-hydroxy-3-methoxy-7α-methyl-1,3,5(10)-estratriene (requires largeamounts of pyrophoric metals and liquid ammonia) and (b) modest overallyields and the need for laborious chromatographic separations of7-methylsteroid intermediates isomeric at C(7). Again, the 3,3-dimethoxy(3,3-dimethyl ketal) derivative is the only type of a steroidal3,3-ketal used for the direct hydrolysis to tibolone—none of theexisting processes for tibolone preparation comprises a hydrolysis stepof other steroidal 3,3-ketal derivatives. Similarly, none of theexisting methodologies for tibolone synthesis has taken advantage of thedeconjugative ketalization reaction in order to form the 5,(10)-doublebond present in tibolone.

Unexpectedly, it has now been found that according to the presentinvention tibolone can be prepared in high yield on the way of a onestep process comprising the hydrolysis of17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketals offormula 2, where:

-   -   (1) each of R₁, R₂, R₃ and R₄ is a hydrogen atom or a C₁₋₄ alkyl        group, or    -   (2) R₁ and R₃ are taken together to form an alicyclic ring        together with the carbon atoms in the dioxolane ring to which        the groups are attached and R₂, R₄ are hydrogen atoms, or    -   (3) R₁ and R₃ are taken together to form an aromatic ring        together with the carbon atoms in the dioxolane ring to which        they are attached, and R₂, R₄ are taken together to form a        chemical bond participating in the aromatic electron system of        the aromatic ring formed by R₁ and R₃.        in the presence of salts of transition metals, salts of lithium        or salts of magnesium;    -   (b) separating        17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one        obtained in step (a) from        17β-hydroxy-7α-methyl-19-nor-17α-pregn-4-en-20-yn-3-one        by-product of formula 3; and    -   (c) converting        17β-hydroxy-7α-methyl-19-nor-17α-pregn-4-en-20-yn-3-one obtained        as a by-product in step (b) to the ketal of formula 2, wherein        R₁-R₄ are defined as above, which is then hydrolyzed to        17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one in        step (a).

This finding of the present invention is even more surprising in lightof the reported process for the synthesis of a derivative of17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one(7α-methylnorethindrone) from a 3,3-ethylenedioxy-5(10)-ene, -4-eneand/or -5-ene precursors (Blye, R. Et al., U.S. Pat. No. 4,308,265).These authors found that the hydrolysis of the 3,3-ethylenedioxy acetalcarried out under acidic conditions gave exclusively7α-methylnorethindrone, which is a conjugated ketone possessing a4-en-3-one structure, and not the 5(10)-en-3-one structure, which isfound in tibolone.

The 3,3-cyclic ketals of formula 2 have never been reported assubstrates for a one-step preparation of tibolone. Prior art alsoincludes other reports on the synthesis of steroidal 4-en-3-ones from3,3-ethylenedioxy-5(10)-ene or -5-ene precursors [EP 0 700 926 A1; U.S.Pat No. 2,806,030; Synth. Commun. 25, 395 (1995)], including a reportwhich addresses the hydrolysis of3,3-ethylenedioxy-15α-hydroxy-7αmethyl-5(10)-estren-17-one, which, inthe presence of hydrochloric acid, afforded15α-hydroxy-7α-methyl-4-estren-3,17-dione [J. Med. Chem. 35, 2113,(1992)]. Other types of acidic conditions used for the hydrolysis ofsteroidal ethylenedioxy ketals, which were not 7-methyl-5(10)-estrenederivatives, include aqueous acetic acid, aqueous acetic acid/Et₂O ormalonic acid/acetone-water [U.S. Pat. No. 3,904,611; GB 2,185,257A; J.Org. Chem. 43, 1821 (1978)]. The presence of the 7α-methyl group isknown to influence the chemistry of estrane derivatives to a largedegree [J. Med. Chem. 35, 2113 (1992) and Steroids 60, 414 (1995)].

Equally unexpectedly, a process for the preparation of structurallydefined 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclicketals of formula 2 has not been put forth to date. Example 3 of U.S.Pat. No. 4,308,265 discloses that3,3-ethylenedioxy-7α-methyl-5(10)-estren-17-one was ethynylated at C(17)and a 17-ethynyl-17-hydroxy compound thus obtained was then hydrolyzedwith dilute hydrochloric acid to a crystalline enone, which wasesterified by heptanoic anhydride to yield 7α-methylnorethindroneenanthate, which is a steroidal 4-en-3-one, and not a 5(10)-en-3-one.The structures of the intermediates in this route to7α-methylnorethindrone enanthate were not supported by anyphysicochemical or other data. Also, no experimental details were givenfor the crucial ketalization step and no purification of the product wasdescribed. Incidentally, the prior art regarding the various positionalisomers of alkenes which may form upon ketalization of 4-en-3-ones [J.Med. Chem. 35, 2113 (1992) and Steroids 60, 414 (1995); SyntheticCommun. 27, 2197 (1997); Recl. Trav. Chim. Pays-Bas 92, 1047 (1973)]teaches that, when the conditions are not carefully controlled, thealternative structures of 3,3-ethylenedioxy-7α-methyl-5-estren-17-one or3,3-ethylenedioxy-7α-methyl-4-estren-17-one are very likely on the wayto 7α-methylnorethindrone esters as described in U.S. Pat. No.4,308,265. Importantly, in the patent U.S. Pat. No. 4,308,265 there isno indication that the hydrolysis of3,3-ethylenedioxy-17βethynyl-17-hydroxy-7α-methyl-5(10)-estrene in thepresence of acid may lead to tibolone.

It has now been found that, according to the present invention,chemically pure and structurally defined17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketals offormula 2 can be prepared in one step from7α-methyl-5(10)-estren-17-one. 3,3-cyclic ketals of formula 4, whereR₁-R₄ are as defined above, by reacting a compound of formula 4 withmetal acetylides in inert solvents while maintaining the reactionmixture temperature in the range from about −50° C. to about +30° C.,followed by a purification procedure, preferably by crystallization,more preferably by crystallization from a mixture of solvents containing0%-50% THF, 0%-50% 1,4-dioxane, 0%-50% toluene and 0%-100% of ethylacetate, and most preferably by crystallization from ethyl acetate,which is found to be particularly efficient in removing any positionalalkene isomers from the 5(10)-alkene product.

Another unexpected finding of the present invention is a process for thepreparation of 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene3,3-cyclic ketals of formula 2, where R₁-R₄ are as defined above, in onestep from 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one and vicinaldiols, in the presence of a protic acid, preferably in the presence of adehydrating agent and a hydrocarbon co-solvent, most preferably in thepresence of a protic acid with pKa less than ca. 1.5, a trialkylorthoformate chosen from the group comprising trimethyl orthoformate,triethyl orthoformate, triisopropyl orthoformate, and, optionally, aco-solvent chosen from the group comprising toluene or xylenes.

The process of the present invention allows for an efficient preparationof tibolone (formula 1, Chart) from3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene orfrom other ketals of the present invention, described by formula 2. Thepractical value of this finding is best reflected by the fact that, incombination with the known synthesis of the compounds of formula 4 [e.g.U.S. Pat. No. 3,928,398; J. Med. Chem. 35, 2113 (1992)], tibolone cannow be obtained in seven synthetic steps from the commercially available19-nortestosterone.

The substrates necessary to accomplish the synthesis of tiboloneaccording to the process of the present invention, are easily available.It has been reported that 7α-methyl-5(10)-estren-17-one 3,3-cyclicketals of formula 4 can be prepared in two synthetic steps from7α-methyl-19-nortestosterone [R₁-R₄=H; J. Med. Chem. 35, 2113 (1992)].The first step of this preparation is a deconjugative ketalizationprocess comprising a reaction of 7α-methyl-19-nortestosterone withethylene glycol in the presence of p-toluenesulfonic acid, affording3,3-ethylenedioxy-17β-hydroxy-7α-methyl-5(10)-estrene. However, othervicinal diols are also known to react with 3-keto steroids [Synthesis501 (1981)] affording 3,3-ketals of a dioxolane structure where thedioxolane ring is substituted with one or more C₁₋₄ alkyl group(s) orthe dioxolane ring is condensed with an alicyclic or an aromatic ring.

The second step of the preparation of 7α-methyl-5(10)-estren-17-one3,3-cyclic ketals of formula 4 [R₁-R₄=H; J. Med. Chem. 35, 2113 (1992)]is an unbuffered PCC oxidation of3,3-ethylenedioxy-17β-hydroxy-7β-methyl-5(10)-estrene. Many alternativemethods for mild oxidation of 17-hydroxy steroids have also beendisclosed (e.g. in patents DE 3,337,179 and EP 0 700 926 A1).

A process for the preparation of 7α-methyl-19-nortestosterone in fourtechnological steps and in a good chemical yield from 19-nortestosteronehas been put forth in U.S. Pat. No. 3,928,398. However, it may readilybe apparent to those skilled in the art that the last two steps of this7α-methyl-19-nortestosterone preparation (1,6-conjugate methylationfollowed by double bond isomerisation with concomitant cleavage of the17-acetate to 17-hydroxyl) can be performed in one reaction vessel, thusshortening the route from 19-nortestosterone to7α-methyl-19-nortestosterone to three technological steps: (a)nortestosterone enolization-peracetylation to3,17β-diacetoxy-3,5-estradiene, (b) bromination-dehydrobromination to17β-acetoxy-4,6-estradien-3-on and (c) 1,6-conjugate methylation(performed e.g. with Me₂CuLi) followed by double bond isomerisation withconcomitant cleavage of the 17-acetate to 17-hydroxyl (performed e.g. bythe addition to the reaction mixture of a KOH/MeOH solution) affording7α-methyl-19-nortestosterone. The purification of7α-methyl-19-nortestosterone from the 7β-methyl isomer is easilyaccomplished by crystallization.

The novel process for tibolone synthesis according to the presentinvention by hydrolysis of 3,3-ketals of formula 2, is presented in theScheme I. It has now been found that the choice of the appropriateconditions for the hydrolysis reaction according to the process of thepresent invention is crucial to the successful synthesis of the desiredproduct. According to the present invention, the reaction can be carriedout in an organic solvent, optionally in the presence of water, and iscarried out under the conditions chosen from two alternative types ofconditions according to the process of the present invention,facilitating the hydrolysis reaction, which are listed below:

(a) under the conditions of the first type, the hydrolysis reaction iscarried out in the presence of an acid, preferably an organic acid ofmedium strength (pKa/_(H2O)=2-5). Appropriate acids are chosen from thegroup including, but not limited to, oxalic acid, acetic acid, fumaricacid, formic acid, malonic acid and pyridinium p-toluenesulfonate. Mostpreferred is formic acid, or

(b) under the conditions of the second type, the hydrolysis reaction iscarried out in the presence of a transition metal salt or a salt oflithium or magnesium, preferably a salt of lithium, iron, magnesium orcopper. Preferred salts are copper(II) sulfate, copper(II) chloride,iron(III) chloride, lithium(I) tetrafluoroborate or magnesium(II)trifluoroacetate. Most preferred is copper(II) sulfate.

According to the present invention, the hydrolysis reaction is carriedout in a mixture of solvents consisting of 0%-99% water and 0%-100% ofan organic solvent selected from a group including, but not limited to:THF, CHCl₃, 1,4-dioxane, CH₂CL₂, acetone, acetonitrile, ethylmethylketone, diethyl ketone, 1,3-dioxolane, 1,2-dimethoxyethane,1,2-diethoxyethane, and 0%-100% of a C₁₋₄ alcohol.

The hydrolysis reaction according to the process of the presentinvention can be carried out at a broad range of temperatures from 0° C.to 200° C., more preferably 15° C.-150° C. and most preferably 30°C.-90° C. The progress of the hydrolysis reaction may be monitored byanalytical methods, preferably by HPLC or TLC on a “reversed phase” suchas a C-18 phase. The reaction time should be sufficiently long to allowfor a complete conversion of the substrate ketal of formula 2, and notfor a substantially longer time. This is important, since after a longerreaction time, the formation of the desired tibolone of formula 1 isaccompanied by the formation of increasing amounts of17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one(7α-methylnorethisterone) of formula 3.

It has now been found that in order to ensure a good purity of tiboloneprepared by the hydrolysis reaction according to the present invention,the ketal (acetal) substrate of formula 2 must be of purity better than90%—if this condition is not fulfilled difficulties with purificationmay offset the benefits of this short synthetic route to tibolone.

According to the present invention, after the usual work-up procedure,the mixture of tibolone and 7α-methylnorethisterone is separated bytechniques known to the skilled in the art, such as by chromatography,by crystallization or by a combination of these techniques.

It has been found that the conditions for the hydrolysis of the ketalsof formula 2 put forth in the present invention ensure high selectivitytoward tibolone as the major reaction product. Typically, tibolone isobtained in a large molar excess compared to 7α-methylnorethindrone,equal at least 2:1, more preferably 4:1, even more preferably 8:1.

The yield of tibolone obtained by this procedure is at least about 50%based on the 5(10)-estrene derivative of formula 2 and typically theyield of tibolone is much better. The amount of the side product formedis up to 20% based on the 5(10)-estrene derivative of formula 2, andtypically it is much less.

According to the process of the present invention,7α-methylnorethisterone of formula 3 can be conveniently reacted with avicinal diol to form the 5(10)-estrene 3,3-ketal derivative of formula2, which can be used again (recycled) in the hydrolysis step accordingto the present invention, leading to tibolone.

The reaction of 7α-methylnorethisterone of formula 3 with a diol iscarried out, according to the process of the present invention, in thepresence of an acid, preferably in the presence of a protic acid ofpKa<1.5, most preferably in the presence of p-toluenesulfonic acid or anacid of a similar strength. Optionally, an organic non-polar solvent isused for the reaction, preferably toluene or xylenes. The reaction mayoptionally be carried out in the presence of a dehydrating agent,preferably a trialkyl orthoformate chosen from the group comprisingtrimethyl orthoformate, triethyl orthoformate, and/or triisopropylorthoformate. According to the present invention, after the usualwork-up procedure, the crude ketal of formula 2 is purified bytechniques known to the skilled in the art, such as by chromatography,by crystallization or by a combination of these techniques. A preferredmethod of purification according to the present invention is bycrystallization, more preferably by crystallization from a mixture ofsolvents containing 0%-50% THF, 0%-50% 1,4-dioxane, 0%-50% toluene and0%-100% of ethyl acetate, and most preferably by crystallization fromethyl acetate, which is now found to be particularly efficient inremoving any positional alkene isomers from the 5(10)-alkene product.

The process of the present invention is, in its principle, appropriatefor production of tibolone on a small plant scale or on a plant scale.The preparation of the new 5(10)-estrene 3,3-ketals of formula 2 and thenew process for their hydrolysis according to the present inventionallow for a reduction in the number of synthetic steps compared to theprior art regarding the synthesis of tibolone from commerciallyavailable steroids. The mild acidic conditions used for the hydrolysisreaction according to the present invention, are easy to apply andcontrol. Moreover, the inconvenient Birch reduction step is eliminated.In addition, according to the process of the present invention,7α-methylnorethisterone of formula 3 (which is also known to be aphysiologically active compound) formed as a side product during thehydrolysis, can be reacted with a diol, which efficiently gives a3,3-ketal of formula 2.

The purification of compounds of formula 2, is substantially facilitatedby the finding of the present invention that the crystallization fromethyl acetate alone, or from ethyl acetate in mixtures with othersolvents, is very efficient in recovering pure compounds of formula 2,and in eliminating any positional double bond isomers. Thus, accordingto the process of the present invention, 7α-methylnorethisterone isrecycled by reaction with a vicinal diol resulting in a compound offormula 2, which is then applied as a substrate for the last, hydrolyticstep of tibolone preparation. This improves the overall chemical yieldof the process of the present invention and lowers the cost of tibolonesynthesis.

Definitions and Conventions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specifications andthe claims.

Definitions

TLC refers to thin-layer chromatography,

RP refers to reversed phase,

RT refers to room temperature (ca. 25° C.),

THF refers to tetrahydrofuran

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support; eluent). Itis understood that the appropriate fractions are pooled, concentratedand dried under vacuum to give the specified compound.

When mixtures of solvents are used, the ratios of solvents used arevolume/volume (v/v).

NMR refers to nuclear magnetic resonance spectroscopy, chemical shiftsare reported in ppm (δ) downfield from tetramethylsilane.

EXAMPLES

It is believed that one skilled in the art can, using the precedingdescription, practice the present invention to its fullest extent. Thefollowing detailed examples describe how to prepare the variouscompounds and/or perform the various processes of the invention and areto be construed as merely illustrative, and not limitations of thepreceding disclosure in any way whatsoever. Those skilled in the artwill promptly recognize appropriate variations from the procedures bothas to reactants and as to reaction conditions and techniques.

Example 1 Preparation of 3,3-ethylenedioxy-7α-methyl-5(10)-estren-17-one(Formula 4, R₁-R₄=H)

Anhydrous NaOAc (analytical grade; 12.2 g), pyridinium chlorochromate(47.0 g, 218 mmol) and anhydrous CH₂Cl₂ (700 mL) were placed in a 2liter flask. The mixture was stirred under nitrogen and cooled to 0° C.A solution of 3,3-ethylenedioxy-17-hydroxy-7α-methyl-5(10)-estrene (36.1g, 108.6 mmol) in anhydrous CH₂Cl₂ (200 mL) was then added over 10 min.The mixture was stirred for 1 hr. Isopropanol (analytical grade, 6.0 mL)was then added and the mixture was stirred for 10 min., after which Et₂O(1.0 L) was added. After stirring for another 10 min., the mixture wasfiltered, the residue was washed with ether (3×150 mL), the filtrateswere combined, anhydrous pyridine (1 mL) was added and the mixture wasleft at room temperature for 2 hrs. Afterwards, it was extracted with10% aqueous KHCO₃ (2×3.00 mL) and dried over anhydrous Na₂SO₄ (280 g).The drying agent was filtered, then washed with CH₂Cl₂ (150 mL). Thefiltrates were combined, concentrated and dried under vacuum. This gavea pale yellow, glassy solid (35 g), which was additionally purified on ashort flash column packed with silica gel (230-400 mesh, 0.4 kg; 15%EtOAc/hexane). The elution of the column with 20% EtOAc/hexane afforded3,3-ethylenedioxy-7α-methyl-5(10)-estren-17-one as a colorless, glassysolid (29.0 g; 80.8%), which crystallized from diisopropyl ether (155mL) to give 3,3-ethylenedioxy-7α-methyl-5(10)-estren-17-one ofanalytical purity (16.81 g); colorless crystals, m.p.: 141.5-143.8° C.;[α]_(D)=+160.50 (28° C., c=1, CHCl₃); ¹H-NMR (CDCl₃) δ 3.98 (4H, m),2.47 (1H, m), 0.87 (3H, s, 18-Me.), 0.83 (3H, d: 7.1 Hz, 7α-Me); ¹³C-NMR(CDCl₃) δ 220.9, 128.0, 124.0, 108.2, 64.5, 64.2, 48.3, 47.3, 41.0,40.5, 40.1, 38.4, 35.8, 31.9, 31.3, 26.7, 26.2, 24.7, 20.9, 14.0, 13.0.

Example 2 Preparation of3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene(Formula 2, R₁-R₄=H)

Potassium t-butoxide (71 g, 0.633 mol) was placed under nitrogen in athree-necked 1 liter flask equipped with a thermometer, a refluxcondenser and a pipette-like inlet for acetylene. Anhydrous THF (550 mL)was added and the mixture was stirred at room temperature for 5 min.,then the flask was immersed in an ice-water bath, the mixture was cooledto 0° C. and, with vigorous stirring, a gentle stream of acetylene wasintroduced. During the addition of acetylene the temperature rose to +8°C. and remained at this level for 2 hrs, after which time it droppedbelow +4° C. At this moment, the stream of acetylene was cut off, and asolution of 3,3-ethylene-dioxy-7α-methyl-5(10)-estren-17-one (28.6 g;86.5 mmol) in anhydrous THF (150 mL) was added with vigorous stirring.The introduction of acetylene was then resumed. The mixture wasvigorously stirred and cooled such that the temperature was maintainedin the range +4 to +80° C. After 4 hrs, the mixture was cautiouslytransferred over 20 min. to a 6 liter reactor, containing a mixture ofsaturated NH₄Cl/H₂O (2.0 L) and toluene (1.0 L), which was vigorouslystirred under nitrogen and cooled to 0° C. After 45 min. of stirring,the reactor was set aside for 1 hr at RT. The phases were then separatedand the organic phase was dried over anhydrous Na₂SO₄ (300 g). Thedrying agent was filtered and washed with EtOAc (200 mL), the filtrateswere combined and concentrated in vacuo. This latter operation wasfacilitated by the addition of ca. 15% v/v anhydrous THF to preventspontaneous crystallization, which was causing foaming. The product wasdried under vacuum and crystallized from hot ethyl acetate (100 mL;cooled to RT and left for 14 hrs) to give pure3,3-ethylenedioxy-17-ethynyl-17-hydroxy-7a-methyl-5(10)-estrene (16.66g, 54%); m.p.: 181-183° C.; [α]_(D)=+46.80° (28° C., c=1, CHCl₃); ¹H-NMR(CDCl₃) δ 3.98 (4H, m), 2.58 (1H, s), 0.85 (3H, s, 18-Me), 0.79 (3H, d:7.1 Hz, 7α-Me); ¹³C-NMR (CDCl₃) δ 128.2, 123.7, 108.3, 87.7, 79.7, 73.7,64.4, 64.1, 47.4, 46.2, 41.4, 41.0, 39.8, 38.9, 38.5, 33.1, 31.4, 27.2,26.2, 25.1, 22.0, 13.0, 12.9.

Example 3 Preparation of17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one (Tibolone, Formula1)

3,3-Ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene (16.2g, 45.4 mmol) was dissolved in anhydrous THF (100 mL). The solution wasstirred at 40° C. under nitrogen, and ethanol (99.8 %; 500 mL) and water(140 mL) were added, followed by 96% formic acid (10.0 mL). After themixture was stirred at 60° C. for 1 hr, methanol (100 mL) and formicacid (5.0 mL) were added and stirring under nitrogen was continued. Thereaction was monitored on C-18 RP TLC plates developed with 10%H₂O/MeOH. After 6 hrs the reaction mixture was poured on a mixture ofwater (1.5 L) and pyridine (50 mL), which was stirred and cooled undernitrogen at +15° C. After 15 min. more water (0.5 L) was added andstirring was continued for another 30 min. The mixture was left at +4°C. for 14 hrs. The precipitate was filtered, dissolved in CH₂Cl₂ (300mL) and extracted with 5% aqueous KHCO₃ (200 mL)). The phases wereseparated, the organic phase was dried over anhydrous Na₂SO₄ (50 g),filtered, concentrated and dried in vacuo. This gave a white solid (14.0g) which was separated using flash chromatography and crystallization.Chromatography was performed on a column packed with silica gel (300 g,230-400 mesh; 20% EtOAc—20% CH₂Cl₂—60% hexane). Crystallization wascarried out from hot ethanol by slowly cooling the solution to RT andleaving it at this temperature for a day. This procedure afforded:

-   -   (a) 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one        (tibolone; 9.04 g, 63.7%) as a white, crystalline powder;        m.p.=165.8-168.8° C.; [α]_(D)=+103.2° (28° C., c=1, EtOH); HPLC        purity of the sample reported herein was determined on a C-18        column using a standardized procedure: R_(t)=8.42 min,        purity=99.12%; ¹H-NMR (CDCl₃; 200 MHz) δ 2.73 (2H, m), 2.59 (1H,        s), 0.88 (3H, s, 18-Me) and 0.84 (3H, d: 7.0 Hz, 7α-Me)—spectrum        in complete agreement with the spectrum obtained for a tibolone        standard; ¹³C-NMR (CDCl₃; 50 MHz) δ 211.4, 129.8, 124.5, 87.6,        79.6, 73.8, 47.4, 46.0, 44.9, 41.7, 39.5, 39.1, 38.9, 38.4,        33.0, 27.4, 27.1, 25.2, 22.0, 13.0, and 12.8, and    -   (b) 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one (formula 3;        2.70 g, 19.0%) as colorless prisms; m.p.: 200.5-202.5° C.;        [α]_(D)=(−)24° (20° C., c=1, CHCl₃); UV λ_(max)=241 nm; ¹H-NMR        (200 MHz; CDCl₃) δ 5.83 (1H, s), 2.57 (1H, s), 0.91 (3H, s) and        0.78 (3H, d: 7.0 Hz) ppm; ¹³C-NMR (50 MHz; CDCl₃) δ 199.6,        165.0, 126.5, 87.5, 79.5, 74.0, 46.9, 45.9, 43.5, 43.3, 43.0,        42.0, 38.8, 36.6, 32.3, 30.7, 26.7 (2C), 22.2, 12.8 and 12.6        ppm.

Example 4 Preparation of 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one (Tibolone, Formula 1).

3,3-Ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene (441mg, 1.24 mmol) and anhydrous ethanol (10 mL) were stirred under nitrogenat 75° C. When the mixture became clear, methanol (5 mL) was added,quickly followed by a solution of CuSO₄×5 H₂O (320 mg, 1.28 mmol) inwater (2 mL). The mixture was stirred under nitrogen while the heatingbath temperature was maintained in the range of 73-76° C. The progressof the reaction was monitored by RP-TLC (C-18; 10% H₂O in MeOH). After4.5 hrs more CuSO₄ ×5 H₂O (51 mg) was added and stirring was continuedfor another 0.5 hr. The reaction mixture was then cooled to +40° C. and,with vigorous stirring, 3% aqueous NaHCO₃ (70 mL) and CH₂Cl₂ (70 mL)were added. After extraction, the phases were separated and the aqueousphase was washed with CH₂Cl₂ (20 mL). The phases were separated, theorganic phases were combined, dried over Na₂SO₄ and concentrated undervacuum. The products were isolated on a flash column packed with silicagel (30 g, 230-400 mesh; 20% EtOAc—10% CH₂Cl₂—70% hexane). The fractionshomogenous on TLC were pooled, concentrated under vacuum and dried to aconstant mass under vacuum. This gave:

-   -   (a) 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estren-3-one        (tibolone; 190 mg, 49%) as a white, crystalline powder; ¹H-NMR        spectrum (200 MHz; CDCl₃) identical with a spectrum obtained for        a tibolone standard, and    -   (b) 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one (formula 3;        22 mg, 5.7%) as a white precipitate; ¹H-NMR spectrum (200 MHz;        CDCl₃) identical with a spectrum obtained for an authentic        sample of 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one.

Example 5 Preparation of3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene(Formula 2, R₁-R₄=H) from17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one

17α-Ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one (3.46 g, 11 mmol) andanhydrous toluene (100 mL) were stirred under nitrogen at 65° C.Anhydrous ethylene glycol (12 mL) was added, followed byp-toluenesulfonic acid monohydrate (0.20 g). The mixture was vigorouslystirred for 2 min., and anhydrous triethyl orthoformate (3.50 mL) wasthen added. The mixture was stirred under nitrogen at exactly 63-65° C.,over 55 min. Powdered NaHCO₃ was then added in a few portions (total2.20 g), the mixture was stirred for 5 min. and anhydrous pyridine (0.50mL) was added. To prevent a loss of material caused by crystallizationduring work-up, THF (25 mL) was added. The mixture was cooled to +50°C., diluted with EtOAc (100 mL) and twice extracted with 10% aqueousKHCO₃ (2×150 mL). The phases were separated, the organic phase wasdiluted with THF (20 mL), the mixture was dried over Na₂SO₄, filteredand concentrated in vacuo to dryness. The crude product (4.1 g) wascrystallized from hot EtOAc (30 mL). The crystallizing solution was leftat RT for 20 hrs, then filtered to give3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene (2.46g, 62%); identical by ¹H- and ¹³C-NMR with an authentic sample of pure3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene.

Although embodiments and examples of the invention have been shown anddescribed, it is to be understood that various modifications,substitutions, and rearrangements of process steps, compounds andelements, as well as other methods for preparing the compounds of theinvention can be made by those skilled in the art without departing fromthe novel spirit and scope of the invention.

1. A process for the preparation of17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one of formula1, which comprises hydrolyzing17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketal offormula 2, where: (1) each of R₁, R₂, R₃ and R₄ is a hydrogen atom or aC₁₋₄ alkyl group, or (2) R₁ and R₃ are taken together to form analicyclic ring together with the carbon atoms in the dioxolane ring towhich the groups are attached and R₂, R₄ are hydrogen atoms, or (3) R₁and R₃ are taken together to form an aromatic ring together with thecarbon atoms in the dioxolane ring to which they are attached, and R₂,R₄ are taken together to form a chemical bond participating in thearomatic electron system of the aromatic ring formed by R₁ and R₃.
 2. Aprocess according to claim 1, which comprises hydrolyzing3,3-ethylenedioxy-17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene.
 3. Aprocess according to claim 1, characterized in that17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one is obtainedin a molar excess to 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one,equal at least 2:1.
 4. A process according to claim 3, characterized inthat 17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one isobtained in a molar excess to17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one, equal at least 4:1. 5.A process according to claim 4, characterized in that17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one is obtainedin a molar excess to 17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one,equal at least 8:1.
 6. A process according to claim 1, where thehydrolysis reaction is carried out in a mixture of an organic solventand water, in the presence of an acid having pKa value in water in therange of between 2 and 5 (pKa/_(H2O)=2-5).
 7. A process according toclaim 1, where the acid is chosen from a group comprising oxalic acid,acetic acid, fumaric acid, formic acid, malonic acid and pyridiniump-toluenesulfonate.
 8. A process according to claim 7, where the acid isformic acid.
 9. A process according to claim 1, characterized in thatthe hydrolysis reaction is carried out in a mixture containing anorganic solvent and water, in the presence of salts of transitionmetals.
 10. A process according to claim 1, characterized in that thehydrolysis reaction is carried out in a mixture containing an organicsolvent and water, in the presence of lithium or magnesium.
 11. Aprocess according to claim 9, where the salt is copper(II) sulfate. 12.A process according to claim 1, characterized in that the hydrolysisreaction is carried out in a mixture of solvents containing 0%-99%water, 0%-100% of a co-solvent selected from a group consisting of THF,CHCl₃, 1,4-dioxane, CH₂Cl₂, acetone, acetonitrile, ethylmethylketone,diethylketone, 1,3-dioxolane, 1,2-dimethoxyethane, 1,2-diethoxyethane,and 0%-100% of a C₁₋₄ alcohol.
 13. A process according to claim 1, wherethe reaction temperature is from about 0° C. to about 200° C.
 14. Aprocess according to claim 1, characterized in that17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one of formula 3 isconverted to a ketal of formula 2, which is then hydrolyzed to17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one.
 15. Aprocess according to claim 14, characterized in that17α-ethynyl-17β-hydroxy-7α-methyl-4-estren-3-one of formula 3 isconverted to a 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-ketalof formula 2 by reaction with a vicinal diol, in the presence of aprotic acid and a hydrocarbon solvent.
 16. A process according to claim15, characterized in that the17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-ketal of formula 2is purified before the hydrolysis step, by crystallization from amixture of solvents containing 0%-50% THF, 0%-50% 1,4-dioxane, 0%-50%toluene and 0%-100% of ethyl acetate, preferably by crystallization fromethyl acetate.
 17. A composition, comprising:17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketal offormula 2, where (1) each of R₁, R₂, R₃ and R₄ is a hydrogen atom or aC₁₋₄ alkyl group, or (2) R₁ and R₃ are taken together to form analicyclic ring together with the carbon atoms in the dioxolane ring towhich the groups are attached and R₂, R₄ are hydrogen atoms, or (3) R₁and R₃ are taken together to form an aromatic ring together with thecarbon atoms in the dioxolane ring to which they are attached, and R₂,R₄ are taken together to form a chemical bond participating in thearomatic electron system of the aromatic ring formed by R₁ and R₃.
 18. Acompound, comprising: 17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene3,3-cyclic ketal of formula 2, where R₁, R₂, R₃, and R₄ are hydrogenatoms.
 19. A compound according to claim 18, of about 90% purity.
 20. Acompound according to claim 18, of purity better than 90%.
 21. A processfor the preparation of pure17α-ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene 3,3-cyclic ketals offormula 2, where R₁-R₄ are hydrogen atoms, characterized in that7α-methyl-5(10)-estren-17-one 3,3-cyclic ketal of formula 4, where R₁-R₄are hydrogen atoms, is reacted with a metal acetylide, in an inertsolvent, while maintaining the temperature of the reaction mixture inthe range from about −50° C. to about +30° C.
 22. A process according toclaim 21, characterized in that, prior to the addition reaction, saidmetal acetylide is generated from acetylene gas, in the same reactionpot in which the addition to 7α-methyl-5(10)-estren-17-one 3,3-cyclicketal of formula 4 will subsequently be carried out.
 23. A processaccording to claim 22, characterized in that the said reaction productof formula 2 is further purified by crystallization from a solventcontaining 50-100% ethyl acetate.
 24. A process according to claim 6,where the acid is chosen from a group comprising oxalic acid, aceticacid, fumaric acid, formic acid, malonic acid and pyridiniump-toluenesulfonate.